Interleukin-1β Induces Blood–Brain Barrier Disruption by Downregulating Sonic Hedgehog in Astrocytes

• Published in: PloS one Vol. 9; no. 10; p. e110024
• Main Authors: Wang, Yue, Jin, Shijie, Sonobe, Yoshifumi, Cheng, Yi, Horiuchi, Hiroshi, Parajuli, Bijay, Kawanokuchi, Jun, Mizuno, Tetsuya, Takeuchi, Hideyuki, Suzumura, Akio
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.10.2014; Public Library of Science (PLoS)
• Subjects: Amyotrophic lateral sclerosis; Animals; Astrocytes; Astrocytes - metabolism; Biology and Life Sciences; Blood; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain; Brain research; CCL20 protein; Cell culture; Cell division; Cell Line; Cell migration; Central nervous system; Chemokines; Chemokines - genetics; Chemokines - metabolism; Conditioning; Cytokines; Disease; Disruption; Down-Regulation; Endothelial cells; Environmental health; Gene Expression; Hedgehog protein; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Homeostasis; IL-1β; Inflammation; Integrity; Interleukin-1beta - physiology; Interleukins; Medical research; Medicine; Medicine and Health Sciences; Membrane permeability; Mice; Microglia; Monocyte chemoattractant protein 1; Multiple sclerosis; Nervous system; Neurological diseases; Paracrine Communication; Parkinson's disease; Pericytes; Permeability; Proteins; R&D; Research & development; Therapeutic applications; Tight Junctions - metabolism; United States > US; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0110024

The blood-brain barrier (BBB) is composed of capillary endothelial cells, pericytes, and perivascular astrocytes, which regulate central nervous system homeostasis. Sonic hedgehog (SHH) released from astrocytes plays an important role in the maintenance of BBB integrity. BBB disruption and microglial activation are common pathological features of various neurologic diseases such as multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Interleukin-1β (IL-1β), a major pro-inflammatory cytokine released from activated microglia, increases BBB permeability. Here we show that IL-1β abolishes the protective effect of astrocytes on BBB integrity by suppressing astrocytic SHH production. Astrocyte conditioned media, SHH, or SHH signal agonist strengthened BBB integrity by upregulating tight junction proteins, whereas SHH signal inhibitor abrogated these effects. Moreover, IL-1β increased astrocytic production of pro-inflammatory chemokines such as CCL2, CCL20, and CXCL2, which induce immune cell migration and exacerbate BBB disruption and neuroinflammation. Our findings suggest that astrocytic SHH is a potential therapeutic target that could be used to restore disrupted BBB in patients with neurologic diseases.